Pediatric cardiomyopathy (CM) is a common cause of death and morbidity. Although multiple etiologies are known, until recently, the majority of cases were termed "idiopathic". Now, it is recognized that CM is familial in 20-50% of adult patients. In dominantly-inherited hypertrophic CM (HCM), single gene defects have been defined. Delineation of genetic causes of pediatric dilated CM, however, is virtually limited to those genes associated with muscular dystrophies. Our laboratory has documented mutations in mitochondrial proteins of the fatty acid oxidation pathways as causes of both HCM, DCM, and sudden expected death. Extensive searches for genetic causes of pediatric M have not been done. Therefore, this proposal will explore the hypothesis that pediatric cardiomyopathy often has a genetic has a genetic etiology, especially secondary to defects in cardiac energy production and develop animal models to determine the molecular pathogenesis of these CMs through four aims. Aim 1 is to systematically evaluate all pediatric cardiomyopathy patients in St. Louis Children's Hospital for familial causes and genetic etiologies, by clinical, morphologic, and biochemical analyses. Aim 2 is to characterize the genetic locus in a St. Louis family with dominantly-inherited DCM, with the long term goal of definition mutations in the responsible gene. Aim 3 is to delineate mutations in nuclear genes encoding the human fatty acid beta-oxidation transporters and enzymes causing pediatric CM, including those in very-long-chain acyl-CoA dehydrogenase, long-chain acyl CoA dehydrogenase, both subunits of the trifunctional protein, and carnitine palmitoyl-transferase II. This aim will test whether genotype phenotype correlations exist for these deficiency states. Aim 4 is to define the pathogenesis of CM in fatty acid oxidation defects through creation of mouse models of deficiency by gene ablation techniques and by physiologic and biochemical characterization of deficient animals. Through delineation of genes causing pediatric cardiomyopathy and analysis of mechanisms of myocardial and analysis of the mechanisms of myocardial dysfunction and sudden death in animal models of these genetic defects, a better understanding of proteins essential for cardiac function and adaptation should be forthcoming.